In cystic fibrosis (CF), mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) unleash a cascade of clinical disorders, including chronic airway infections, systemic inflammation, microbial virulence, diabetes, malnutrition and liver disease. Great progress has been made in some areas of disease, and CFTR modulators provide dramatic benefits to some patients. Still, there is growing evidence of the interconnections among the diverse aspects of lung and gut dysbiosis and their contributions to CF pathogenesis. Furthermore, as patients are enjoying longer lives, formerly rare symptoms are becoming more common. Thus, there is a pressing need to both understand and systematically treat the functional relationships between CFTR function, commensal and pathogenic microbes, metabolic states, and innate and acquired immune responses. The Dartmouth CF Research Center (DartCF) will leverage: 1) our well-funded, highly collaborative CF research base in epithelial biology, CFTR correction, airway infections, host-microbe interactions and antimicrobial strategies; 2) a broad pool of new faculty interested in CF; 3) program-grant partners; 4) substantial institutional investments in CF; and 5) regional and national collaborations with complementary skills and datasets. Our aims are: 1) to catalyze new research directions in CF basic and translational research; 2) to develop integrative strategies to understand and address CF pathobiology; 3) to create new research tools and support CF research through outstanding shared services; and 4) to build research capacity in CF locally, regionally, and nationally. We will focus P30 resources on 1) pioneering a national repository for CF datasets and forging collaborations between CF and data-science researchers to mine these datasets for systems-level perspectives and 2) building on unique Dartmouth longitudinal patient cohorts to explore microbial colonization and infection in the gut and airway, and the effects of existing therapies. A key theme is that dysbiosis in the lung and gut are deeply interconnected, and that parallel investigations, coupled by powerful new data-science strategies can find new therapeutic approaches by understanding this complex underlying biology. In parallel, we will leverage our research base to support early-stage preclinical target development. DartCF will support a variety of mechanisms to achieve our goals. First, we will fund pilot and feasibility awards to develop new research and translational opportunities and to recruit new faculty members to the Center. Second, we will fund three scientific cores to support studies in CF pathobiology: an Epithelial-Microbe Interaction Core (EMIC), a Translational Research Core (TRC), and an Applied Bioinformatics & Biostatistics Core (ABBC). Finally, we will support an Enrichment and Research Administration Core to foster an interactive scientific community, sponsor retreats and courses, and track program progress. These efforts will identify new CF therapeutic opportunities, develop novel interventions, monitor the resulting changes body-wide, and track outcomes. DartCF will intensify the translation of research into improved CF outcomes at Dartmouth, regionally, and nationwide.